1. Field of The Invention
This invention lies in the field of techniques and compositions for hemodialysis and related matters.
2. State of the Art
The vital functions of highly developed organisms are closely dependent on the internal aqueous medium and on the maintenance in it of extreme constancy of chemical and physical properties.
It has long been recognized that all animal intracellular and extracellular body fluids contain inorganic electrolytes, and that these electrolytes are involved in, and profoundly influence, various life processes. Attempts to make artificial electrolyte fluids which may bathe tissues or be administered to the human blood stream have been known since about 1880, and, although modern analytical tools and procedures have clarified compositional details of blood electrolytes, the use of various aqueous electrolytes solutions for in vivo purposes in human medicine and related fields has been extant for approximately one hundred years.
Those inorganic electrolytes characteristically found in normal human blood serum at respective concentration levels above about 1 millimolar per liter of concentration are shown below in Table 1. Also, for comparative purposes, in Table II are shown some representative compositions of various aqueous electrolyte solutions that have been previously prepared and used for in vivo (including dialysis) purposes. In general, the philosophy behind the formulation of aqueous electrolyte solutions for in vivo use has been that such should mimic or closely resemble the chemical composition of electrolytes in blood and plasma.
An electrolyte is a substance (usually a salt, acid or base) which in solution dissociates wholly or partly into electrically charged particles known as ions (the term is also sometimes used in the art to denote the solution itself, which has a higher electrical conductivity than the pure solvent, e.g. water). The positively charged ions are termed cations while the negatively charged ions are termed anions. Strong and weak electrolytes are recognized. The dissociation of electrolytes is very markedly dependent on concentration; it increases with increasing dilution of the solutions. Because of dissociation considerations, the term "sigma" or the greek letter for sigma (".SIGMA.") is sometimes employed herein as a prefix to designate the total presence of a specified material, such as an electrolyte, whether or not all of the material is in an ionic form complexed with a heavy metal, or regardless of charge on the material in a given solution. A pair of brackets ([]) indicates the free concentration of the substance indicated as opposed to that bound to tissue components, such as proteins.
TABLE 1 __________________________________________________________________________ Chemical Content of the Millimolar Components of Normal Human Blood Serum. (From N Eng J Med 1970; 283: 1276-1285) Values are given as ranges in units of m moles/L serum, mEq/L serum, or mEq/L serum H.sub.2 O mEq/L serum H.sub.2 O Cations m mol/L serum mEq/L serum (assuming 935 ml H.sub.2 O/L __________________________________________________________________________ serum) Na.sup.+ 136-145 136-145 145-155 K.sup.+ 3.5-5.0 3.5-5.0 3.7-5.3 Ca.sub.total 2.1-2.6 -- -- free [Ca.sup.2+ ].sup.(1) [1.065] [2.12] [2.12] 0.035 0.07 0.0.7 Mg.sub.total 0.75-1.25 -- -- free [Mg.sup.2+ ].sup.(2) [0.53] [1.06] [1.06] Total mEq Cations 142.7-153.2 152.6-163.8 Total mOsmoles 141-151.6 Anions Cl.sup.- 100-106 100-106 107-113 HCO.sub.3.sup.- 26-28 26-28 27.8-29.9 .SIGMA. Pi.sup.1.8- 1-1.45 1.8-2.6 1.9-2.8 .SIGMA. SO.sub.4.sup.2- 0.32- 0.94 0.32-0.94 0.34-1.0 Metabolic acids.sup.-(3) *2.0-4.0 *2.0-4.0 *2.1-4.3 Apparent Total mEq Anions 130-141.5 139.1-151 Total mOsmoles 141-151.6 Apparent Anion Gap 12.7-11.7 11.7-11.1 Polyanions Albumin.sup.20-(4) 0.58-0.73 11.8-14.8 12.6-15.8 Ca--Mg Albuminate.sup.17.7-(5) 0.58-0.73 10.3-12.9 11.0-13.7 Non Ionics (fasting) 3.9-5.6 Glucose (fed).sup.(6) 7-11 Urea (5-25 mg %) 2.9-8.9 Globulins (3 g %) *0.2 CO.sub.2 + H.sub.2 CO.sub.3 0.99-1.39 Grand Total mOsmoles 279-314 Total mEq Cations 142.7-153.7 152.6-163.8 Total mEq Anions 140.3-154.4 150.0-165.1 __________________________________________________________________________ .sup.(1) Free [Ca.sup.2+ ] from Burritt M F, Pierides A M, Offord k P. Mayo Clin Proc 55, 606-613, 1980. .sup.(2) Free [Mg.sup.2+ ] from Walser M. J Clin Invest 40, 723, 1961 .sup.(3) Range of major metabolic acids above 0.1 .differential.M are 1lactate, pyruvate, acetoacetate, ca hydroxybutyrate. Veech R L unpub. .sup.(4) The charge on albumin at pH 7.365 in 0.15 M NaCl is -20.5. Tanford C. J Am Chem Soc 72, 441-451, 1950) .sup.(5) Considering the binding constants of albumin for Ca.sup.2+ and Mg.sup.2+, the charge on albumin in serum may be estimated to be between 17-18. (See Veloso D, Oskarson M A, Guynn R, Veech R L. J Biol Chem 248, 4811-4819, 1973. .sup.(6) Fed glucose values are from Veech R L. Unpublished observations.
Contemporarily, a large number of different aqueous electrolyte solutions are prepared, sold in commerce, and used as in vivo fluids, including dialysis (both hemo- and peritoneal).
In the original hemodialysis solutions, attempts were made to duplicate Krebs-Henseleit as Table II shows. These original hemodialysis systems were open however and loss of CO.sub.2 lead to precipitation of Ca as CaCO.sub.3. The original dialysis solutions contained excessive Cl.sup.- ion in excess of Na.sup.+ to overcome the "anion gap". The term "anion gap" is used to connote the difference in milliequivalents/liter between the apparent sum of routinely measured inorganic cations in plasma and the apparent sum of routinely measured inorganic anions in plasma. The law of electrical neutrality of solutions states that such a term has no real physical meaning, but the term is widely used and accepted.
In 1949, the use of high concentrations of acetate as a metabolizable organic anion was advocated (Mudge, G. H., Mannining, J. A., Gilman, A. Proc. Soc. Exptl. Biol. Med. 71, 136-138, 1949). This idea led in 1964 to the advocacy of the use of 35-45 mM (millimolar) acetate in commercial hemodialysis fluids (Mion, C. M., Hegstrom, R. M., Boen, S. T., Scribner, B. H. Trans. Am. Soc. Artif. Internal Organs10, 110-113, 1964).
In 1981, (Bjaelder, Nephron 27, 142-145, 1981) advocated that use of 38.6 mM acetate instead of 32.6 mM acetate on the grounds that "acetate" represented an equivalent to bicarbonate. Bjaelder showed that the use of 32.6 mM acetate in hemodialysis left patients in chronic acidosis while 38.6 mM acetate did not. He cites the difference in acetate concentration as the cause.
TABLE II __________________________________________________________________________ Prior Art Hemodialysis Fluids. For recent discussion see Parsons FM, Stewart WK. Composition of Dialysis Fluid. In: Replacement of Renal Function by Dialysis (Drucker W, Parsons FM, Maher JP, eds.) Martinus Nijhoff, Hingham, pp 148-170, 1983. __________________________________________________________________________ Units 2d6 2d7 2a16 2a17 2a18 2a19 2b2 2b3 __________________________________________________________________________ Normal Plasma N.E.J.H. Scribner's Commercial Bjaelder Bjaelder Kraut COBE 283, 1285 Kolff Brigham Acetate Acetate "Low" Acet. "High" Acet. HCO.sub.3 -Acetic HCO.sub.3 -Acetic mmoles 1970 1947 1952 1964 1981 1981 1981 Acid, 1981 Acid __________________________________________________________________________ L fluid Na 136-145 126 140 135 140 134 136 140 135 K 3.5-5.0 5.6 4 1.5 2 2.2 2.2 2 2 Ca 2.1-2.6 1.0 1.25 1.25 0.875 1.84 1.91 1.75 1.5 free [1.06] [Ca2+] Mg 0.75-1.25 0.5 0.5 0.375 0 0 -- 0.375 free [0.53] [Mg2+] mEq 142.7-153.2 133.6 147.5 140 144.5 139.88 142.02 145.5 140.75 Cations Cl 100-106 109 120.7 105 106 107.28 103.82 107 106.5 HCO.sub.3 26-28 23.9 26.8 33 33 Pi 1-1.45 SO.sub.4 0.32-0.94 L- 0.6-1.8 lactate pyruvate Lact/pyr D B OH- butyrate aceto- acetate B HB/ acac acetate 35 38.5 32.6 38.2 Other 2 HAcetate 2 HAcetate ?3.5 gluconate mEq 128.7-139.4 132.9 147.5 140 144.5 139.88 142.02 145.5 141.5 anions Na/Cl 1.28-1.45 1.16 1.16 1.29 1.32 1.25 1.31 1.31 1.27 Glucose 3.9-5.6 76-151 10 0 0 0 0 0 0 or others CO.sub.2 0.99-1.39 0 1.24 0 0 0 0 .about.1.3 .about.1.3 pH 7.35-7.45 .about.8.6 7.4 .about.5.5-6.5 .about.5.5-6.5 .about.6.7 .about.6.7 .about.7.4 .about.7.4 mOsm 285-295 343-418 304.8 278.25 287.75 277.92 282.97 289.3 280.4 __________________________________________________________________________ 2d6 Kolff W J. New Ways of Treating Uremia, J&A Churchill, London, 1947 2d7 Murphy W P, Swan R C, Walter C, Weller J M, Merrill J P. J Lab Clin Med 40: 436, 1952. Essentially Krebs Henseleit, but with lower Mg and Ca. 2a16 Mion C M, Hegstrom R M, Boen S T, Scribner B H. Trans Am Soc Artif intern Organs 10: 110-113, 1964 2a17 Made in concentrates by numerous manufactures. The mean concentrations used are given in 2d17 according to Parsons F M and Stewar W K, listed above in title. 2a18 Bjaelder et al Nephron 27: 142-145, 1981. "Low" acetate leaves the patients acidotic, "high" acetate leaves them in normal. Bjaelder's interpretation for the reasons for the acidosis are incorrect. 2b6 Kraut J et al. Clin Neph 15: 181, 1981. Used HCO.sub.3 and acetic acid. 2b3 Commercial source. COBE Laboratories, 1201 Oak Street, Lakewood Colorado.
As we will show here, the reason "high acetate" corrects acidosis is that the Na:Cl ratio in Bjaelder's fluid was 1.31 in the high acetate and 1.25 in low acetate. Bjaelder or clinicians in general were unaware of the importance of this. Nevertheless, many clinical observations have suggested acetate dialysis leads to numerable complications as recent editorials in the British Med. J. 287, 308-309, 1983 questioning the use of acetate dialysis indicate. However until now, no reasonable alternative to acetate dialysis has been devised, nor have the physical chemical and metabolic laws governing dialysis been clearly presented.
In addition to acetate and HCO.sub.3.sup.-, the current reference work "Facts and Comparisons" indicates various commercial peritoneal dialysis fluids which contain dl-lactate anion. (Table III)
All of the prior art dialysis solutions (with or without nutrients) as exemplified in Table II and III are now believed to lead to undesirable and pathological consequences particularly through extended usage.
In addition to failing to solve the anion gap problem (or to provide a normal milliequivalent ratio of sodium cation to chloride anions) without causing profound and adverse physiological effects (including disruption of normal redox state and normal phosphorylation potential), many prior art aqueous electrolyte solutions for in vivo usage fail to have a pH which approximates the pH of mammalian intracellular and extracellular fluids, especially plasma or serum.
TABLE III __________________________________________________________________________ Prior Art Peritoneal Dialysis Solutions The compilation of solutions are taken from: Facts and Comparisons J. B. Lippincott, 111 West Port Plaza, Suite 423, St Louis, Mo. 63146, October, 1982, p. 705-706. Indication: Acute renal failure or exacerbation of chronic renal failure; acute poisoning by dialyzable toxins; acute pulmonary edema; intractable peripheral edema; anasarca; endogenous intoxication such as hyperkalemia, hyperuricemia, hypercalcemia, and uremia; hepatic coma, especially with hepatorenal syndrome. Osmo- Dex- larity trose Electrolyte content given in mEq/liter mOsm/ How Product and Distributor g/liter Na.sup.+ K.sup.+ Ca.sup.++ Mg.sup.++ Cl.sup.- Lactate Acetate liter Supplied __________________________________________________________________________ Dianeal w/1.5% Dextrose (Travenol) 15 141 3.5 1.5 101 45 366 In 1000 and 2000 ml. Dianeal PD-2 w/1.5% Dextrose (Travenol) 15 132 3.5 0.5 96 40 346 In 2000 ml. Dianeal 137 w/1.5% Dextrose (Travenol) 15 132 3.5 1.5 102 35 347 In 2000 ml. Inpersol w/1.5% Dextrose (Abbott) 15 132 3.5 1.5 99 35 344 In 1000 and 2000 ml. Peridial 11/2-D (Cutter) 15 133 3.5 1.5 102 35 348 In 1000 and 2000 ml. Peritoneal Dialysis w/1.5% Dextrose-Low 15 131 3.4 1.5 100 35 345 In 1000 and Sodium (American-McGaw) 2000 ml. Dianeal K w/1.5% Dextrose (Travenol) 15 141 4 3.5 1.5 105 45 374 In 1000 ml. Dianeal K-141 w/1.5% Dextrose (Travenol) 15 132 4 3.5 1.5 106 35 355 In 2000 ml. Peritoneal Dialysis w/1.5% Dextrose- 15 140 4 4.0 1.5 105 45 375 In 2000 ml. Potassium (American McGaw) Peritoneal Dialysis w/1.5% Dextrose 15 141 4.0 1.5 103 45 370 In 1000 and (American McGaw) 2000 ml. Dianeal PD-2 w/2.5% Dextrose (Travenol) 25 132 3.5 0.5 96 40 396 In 2000 ml. Dianeal PD-2 w/4.25% Dextrose (Travenol) 42.5 132 3.5 0.5 96 40 485 In 2000 ml. Dianeal w/4.25% Dextrose (Travenol) 42.5 141 3.5 1.5 101 45 505 In 2000 ml. Dianeal 137 w/4.25% Dextrose (Travenol) 42.5 132 3.5 1.5 102 35 486 In 2000 ml. Inpersol w/4.25% Dextrose (Abbott) 42.5 132 3.5 1.5 99 35 484 In 2000 ml. Peridial 41/2-D (Cutter) 42.5 133 3.5 1.5 102 35 487 In 2000 ml. Peritoneal Dialysis w/4.25% Dextrose-Low 42.5 131.5 3.4 1.5 100 35 485 In 2000 ml. Sodium (American McGaw) Dianeal K-141 w/4.25% Dextrose (Travenol) 42.5 132 4 3.4 1.5 106 35 494 In 2000 ml. Peritoneal Dialysis w/4.25% Dextrose 42.5 141.5 4.0 1.5 103 45 510 In 2000 ml. Peritoneal Dialysis Concentrate w/30% D* 15 130 3.5 1.0 102 34.5 345 In 2000 ml. (American McGaw) Peritoneal Dialysis Concentrate w/50% D* 25 130 3.5 1.0 102 34.5 395 In 2000 ml. (American McGaw) Peritoneal Dialysis Concentrate w/30% D* 15 118.5 3.5 1.0 90.5 34 320 In 2000 ml. Low Sodium (American McGaw) Peritoneal Dialysis Concentrate w/50% D* 25 118.5 3.5 1.0 90.5 34 370 In 2000 __________________________________________________________________________ ml. *Concentration of formulation after dilution with 10 parts water.
In my copending U.S. patent applications filed on even date herewith (identified by U.S. Ser. Nos. 747,292; 747,858; and 748,232) I provide new electrolyte solutions and improved methods for their use which overcome such prior art problems and which not only tend to achieve a normal plasma milliequivalent ratio of sodium cations to chloride anions, but also tend to achieve a normalization of plasma pH and a normalization of the cellular redox state and the cellular phosphorylation potential. Also, these new solutions and methods permit one to avoid usage of the previously employed carboxylic anions, such as acetate, or d,l-lactate alone, which cause adverse effects. The entire teachings and contents of such copending applications I incorporate herein by reference
The electrolyte solutions and methods described in such copending application utilize, as above indicated, individual electrolyte concentrations which, in accord with prior art practice, closely resemble (and are in fact intended to closely resemble) the chemical composition of electrolytes in mammalian blood and plasma.
Alternatively it has recently been advocated that the composition of dialysis fluid in the future should resemble that of intercellular fluid (See Parson, F. M. & Stewart, W. K. in Replacement of Renal Function bv Dialysis (1983) (Drukker, W., Parsons, F. M. & Maher, J. F. eds) pp 148-170, Martin Nijhoff, Hingham).
As will be clear from the disclosures made here, both the view that hemodialysis fluid should mimic plasma or intercellular electrolyte composition is incorrect Rather, hemodialysis fluid electrolyte composition, which will always contact body cells by the media of blood plasma, must contain a precisely calculated degree of deviation from normal in order to achieve electrolyte normality in plasma after blood hemodialysis. The extent and direction of that deviation is determined by the charge and concentration of the non-permeant (Donnan-active) material on the inside (blood side) of the dialysis membrane. In practice, dialysis membranes have pores of average size of 10,000 M. W. The only charged non-permeant material left inside the dialysis cartridge (on the blood side) in a counter-current dialysis are the plasma proteins albumins, globulin and blood cells. As a reasonable approximation, one may take the entire charge as residing on serum albumin because of its very negative isoelectric point. By carefully controlling the pH of the dialysis bath, the clinician may even determine the magnitude of the charge. By then solving a multicomponent, equipressure Donnan equilibrium equation (equation 2 herewith provided) the clinician may then pick precisely the dialysis fluid required by the patient's clinical condition.
In addition to the cause, I have now discovered how to correct the composition of a hemodialysis fluid so that normal concentrations of blood (plasma) inorganic electrolytes can be maintained during hemodialysis. Furthermore, I have discovered a quantitative relationship between hemodialysis so as to produce desired or predictable results. No prior art capability of this sort is believed to have exicted.
Apart from the foregoing discoveries, I have further now discovered how to control the rate at which blood (plasma) concentrations materials are changed during a hemodialysis procedure. In the prior art, such rate of change with respect to time has always conformed to a hyperbolic first order rate equation (as hereinbelow explained). In the present invention, method and apparatus are provided which permit one to linearize the rate of change. In addition new compositions are provided which can be regarded as enhancing the utility of such method and apparatus. Nothing in the prior art is believed to suggest such discoveries.